Heat shock proteins (HSPs) are a class of chaperone proteins that are up-regulated in response to elevated temperature and other environmental stresses, such as ultraviolet light, nutrient deprivation, and oxygen deprivation. HSPs act as chaperones to other cellular proteins (called client proteins) and facilitate their proper folding and repair, and aid in the refolding of misfolded client proteins. There are several known families of HSPs, each having its own set of client proteins. The Hsp90 family is one of the most abundant HSP families, accounting for about 1-2% of proteins in a cell that is not under stress and increasing to about 4-6% in a cell under stress. Inhibition of Hsp90 results in degradation of its client proteins via the ubiquitin proteasome pathway. Unlike other chaperone proteins, the client proteins of Hsp90 are mostly protein kinases or transcription factors involved in signal transduction, and a number of its client proteins have been shown to be involved in the progression of cancer.
Hsp90 has been shown by mutational analysis to be necessary for the survival of normal eukaryotic cells. However, Hsp90 is over expressed in many tumor types indicating that it may play a significant role in the survival of cancer cells and that cancer cells may be more sensitive to inhibition of Hsp90 than normal cells. For example, cancer cells typically have a large number of mutated and overexpressed oncoproteins that are dependent on Hsp90 for folding. In addition, because the environment of a tumor is typically hostile due to hypoxia, nutrient deprivation, acidosis, etc., tumor cells may be especially dependent on Hsp90 for survival. Moreover, inhibition of Hsp90 causes simultaneous inhibition of a number of oncoproteins, as well as hormone receptors and transcription factors making it an attractive target for an anti-cancer agent. In fact, benzoquinone ansamycins, a family of natural products that inhibit Hsp90, has shown evidence of therapeutic activity in clinical trials.
Angiogenesis is a fundamental process of generating new blood vessels (neovasculature) in tissues or organs. Although angiogenesis is necessary for organ growth and repair, uncontrolled angiogenesis is involved with or associated with many diseases or disorders. (e.g. cancers, macular degeneration, autoimmune diseases, etc.) As such, angiogenesis has become a target for the treatment of these diseases. Ferrara, N., et al., Nature 438:15 967-974 (2005).
Angiogenesis is controlled by a number of growth factors and cell-adhesion molecules in endothelial and mural cells. Ferrara, N., et al., Nature 438:15 967-974 (2005). Among these, VEGF-A (vascular endothelial growth factor-A) and its receptors have been widely studied and characterized. Ferrara, N., et al., Nature 438:15 967-974 (2005). It is believed that Hsp90 chaperones a number of proteins in the angiogenic cascade. Sanderson, S., et al., Mol Cancer Ther 5(3) 522-32 (2006). Data has shown that VEGFR-2 (VEGF receptor) and other VEGFRs are Hsp90 client proteins. Sanderson, S., et al., Mol Cancer Ther 5(3) 522-32 (2006).
A number of VEGF inhibitors are approved or currently in clinical trials. Carmeliet, P., Nature 438:15 932-936 (2005). Clinical trials have shown that the current angiogenesis therapies have a number of limitations, including being ineffective as a monotherapy and anti-angiogenic resistance. Carmeliet, Nature 438:15 932-936 (2005). Therefore, a need exists for new therapeutics that reduce or overcome the limitations of currently used anti-angiogenic agents.